1β-Methylcarbapenem compounds exhibit excellent antimicrobial activity against a wide range of pathogenic microbes and have excellent stability in vivo. Thus, 1β-methylcarbapenem compounds are one of the antimicrobial agents that are attracting most of the attention. Therefore, recently, energetical research and development has been conducted on drugs for oral administration. A currently commonly used process for producing a 1β-methylcarbapenem compound for oral administration will be described below.
According to a production process described, for example, in Japanese Unexamined Patent Application Publication No. 8-53453 and the Journal of Antibiotics (J. Antibiot.), 429-439, 1997, a compound represented by general formula (7):
is allowed to react with any of various thiol compounds (R—SH) to synthesize a compound represented by general formula (8):
(wherein R represents a thiol residue); the p-nitrobenzyl group, which is a protecting group, is eliminated, for example, by hydrogenolysis or by reduction using zinc dust to convert the compound (8) into a compound represented by general formula (9):
(wherein R represents a thiol residue); and the carboxylic moiety of the resulting compound (9) is subjected, for example, to pivaloyloxymethylation to produce a compound represented by general formula (10):
(wherein R represents a thiol residue, and But represents a tert-butyl group).
Examples of the compound represented by general formula (10) include a compound represented by general formula (11):
which is described in the Japanese Unexamined Patent Application Publication No. 8-53453 and Japanese Unexamined Patent Application Publication No. 10-195076; a compound represented by general formula (12):
which is described in the Journal of Antibiotics (J. Antibiot. 429-439, 1997, and Japanese Unexamined Patent Application Publication No. 10-130270; and a compound represented by general formula (13):
which is described in Japanese Unexamined Patent Application Publication No. 10-152491. All of these compounds are synthesized by the-process described above.
However, in order to synthesize a 1β-methylcarbapenem compound for oral administration by the process described above, replacement of a protecting group of carboxylic acid is required, and a multistep reaction must be carried out, thus being ineffective. Moreover, a relatively expensive thiol compound, which remains as a thiol residue in the end product, is used at the initial step of synthesis, thus being disadvantageous in terms of production cost and giving rise to a problem.
Furthermore, Japanese Unexamined Patent Application Publication Nos. 8-59663 and 2000-344774 each describe a process in which from a compound represented by general formula (14):
(wherein R4 represents a protecting group of the hydroxyl group, R5 represents a thiol residue contained in the reaction product 1β-methylcarbapenem compound, and R6 represents an organic group), a compound represented by general formula (15):
(wherein R4, R5, and R6 are the same as above; and R7, R8, and R9 each represent a lower alkoxy group having 1 to 4 carbon atoms; or one of R7, R8, and R9 represents an alkyl group having 1 to 4 carbon atoms and the remaining two of R7, R8, and R9 each represent a lower alkoxy group having 1 to 4 carbon atoms) is synthesized, and the compound (15) is cyclized to produce a compound represented by general formula (16):
(wherein R4, R5, and R6 are the same as above)
However, in this production process, as in the process previously described, a relatively expensive thiol compound, which remains as a thiol residue in the end product, is used at the initial step of synthesis, thus being disadvantageous in terms of production cost and giving rise to a problem.
The Journal of Organic Chemistry (J. Org. Chem) 61, 7889-7894, 1996, and Japanese Unexamined Patent Application Publication No. 5-279367 each describe a compound represented by formula (17):
(wherein Me represents a methyl group, and But is the same as above). It can be conceived that a 1β-methylcarbapenem compound may be derived from this compound through reaction with any of various thiol compounds and deprotection of the hydroxyl group. However, in the compound (17), since the protecting group of the hydroxyl group is a tert-butyldimethylsilyl group, a reaction reagent that may affect the other functional groups must be used for the deprotection of the hydroxyl moiety, as exemplified in Protective Groups in Organic Synthesis (J. Wiley & Sons, New York), 44-46, 1981. Thus, there is a problem in terms of yield, etc. Although the present inventors have examined various methods for deprotection, it has not been possible to perform the deprotection easily and efficiently.
Under these circumstances, it has been desired to develop a common intermediate capable of producing 1β-methylcarbapenem compounds efficiently and advantageously in terms of production cost.